title: Taking pain out of NGF: a "painless" NGF mutant, linked to hereditary sensory autonomic neuropathy type V, with full neurotrophic activity.
abstract: During adulthood, the neurotrophin Nerve Growth Factor (NGF) sensitizes nociceptors, thereby increasing the response to noxious stimuli. The relationship between NGF and pain is supported by genetic evidence: mutations in the NGF TrkA receptor in patients affected by an hereditary rare disease (Hereditary Sensory and Autonomic Neuropathy type IV, HSAN IV) determine a congenital form of severe pain insensitivity, with mental retardation, while a mutation in NGFB gene, leading to the aminoacid substitution R100W in mature NGF, determines a similar loss of pain perception, without overt cognitive neurological defects (HSAN V). The R100W mutation provokes a reduced processing of proNGF to mature NGF in cultured cells and a higher percentage of neurotrophin secreted is in the proNGF form. Moreover, using Surface Plasmon Resonance we showed that the R100W mutation does not affect NGF binding to TrkA, while it abolishes NGF binding to p75NTR receptors. However, it remains to be clarified whether the major impact of the mutation is on the biological function of proNGF or of mature NGF and to what extent the effects of the R100W mutation on the HSAN V clinical phenotype are developmental, or whether they reflect an impaired effectiveness of NGF to regulate and mediate nociceptive transmission in adult sensory neurons. Here we show that the R100 mutation selectively alters some of the signaling pathways activated downstream of TrkA NGF receptors. NGFR100 mutants maintain identical neurotrophic and neuroprotective properties in a variety of cell assays, while displaying a significantly reduced pain-inducing activity in vivo (n = 8-10 mice/group). We also show that proNGF has a significantly reduced nociceptive activity, with respect to NGF. Both sets of results jointly contribute to elucidating the mechanisms underlying the clinical HSAN V manifestations, and to clarifying which receptors and intracellular signaling cascades participate in the pain sensitizing action of NGF.
authors.affiliation: European Brain Research Institute, Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Capsoni
authors.forename: Sonia
authors.initials: S
authors.lastname: Covaceuszach
authors.forename: Sara
authors.initials: S
authors.lastname: Marinelli
authors.forename: Marcello
authors.initials: M
authors.lastname: Ceci
authors.forename: Antonietta
authors.initials: A
authors.lastname: Bernardo
authors.forename: Luisa
authors.initials: L
authors.lastname: Minghetti
authors.forename: Gabriele
authors.initials: G
authors.lastname: Ugolini
authors.forename: Flaminia
authors.initials: F
authors.lastname: Pavone
authors.forename: Antonino
authors.initials: A
authors.lastname: Cattaneo
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics / Q000502:physiology; D000818:Animals; D001120:Arginine / Q000235:genetics; D041702:BALB 3T3 Cells; D002478:Cells, Cultured; D002642:Chick Embryo; D020022:Genetic Predisposition to Disease; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D008297:Male; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism / Q000502:physiology; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016716:PC12 Cells; D010146:Pain / Q000235:genetics* / Q000378:metabolism; D058748:Pain Perception / Q000502:physiology*; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism / Q000502:physiology; D014364:Tryptophan / Q000235:genetics
chemical_list: D050505:Mutant Proteins; D009414:Nerve Growth Factors; D020800:Receptor, Nerve Growth Factor; D014364:Tryptophan; D001120:Arginine